PROJECT SUMMARY/ABSTRACT: Signal processing in central auditory pathways depends both on acoustic information transmitted from the auditory periphery and on contextual modulation by distributed brain circuits. Healthy hearing throughout the lifespan relies on the ability to adaptively modify central auditory gain under conditions of ambiguous or degraded acoustic information, such as in noisy environments or after hearing loss. Auditory perception is also influenced by where we look and what we pay attention to, but the mechanisms mediating these contextual effects are poorly understood. Increasing evidence indicates that neural circuits outside of the classical auditory pathways may be particularly important for adaptive gain control in the auditory system. This proposal focuses on the role of the cerebellum, a brain structure historically associated with motor control but more recently recognized for its involvement in optimizing sensory processing. The long-term goal of this exploratory project is to identify the influence of the cerebellum on auditory function, with a particular interest in harnessing cerebellar plasticity mechanisms for therapeutic improvements in hearing. Little is known about the anatomical substrates or physiological effects of the cerebellum on the auditory system. The specific aims of the proposed research are to (1) Identify the neural circuit substrates for cerebellar modulation of the auditory system and (2) Examine the physiological influence of the cerebellum on midbrain auditory activity. Experiments in Aim 1 will take advantage of modern viral anterograde, retrograde, and transsynaptic circuit tracing reagents to identify brainstem and thalamic neurons that are anatomically positioned to connect the cerebellum with the inferior colliculus. Aim 2 will leverage optogenetic stimulation of the cerebellum to assess the physiological influence of manipulating cerebellar activity on spontaneous firing and auditory evoke responses in inferior colliculus neurons. This research will lay the foundation for understanding the circuits, mechanisms, and functional effects of cerebellar-auditory interactions. There are strong clinical implications for adaptive cerebellar control of hearing, as non-invasive cerebellar stimulation could provide a new therapeutic strategy for improving auditory sensitivity after hearing loss.